The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome

Area of Science:

• Genetics
• Molecular Biology
• Neurodevelopmental Disorders

Background:

• Rett syndrome is caused by mutations in the Methyl-CpG binding protein 2 (MECP2) gene.
• Variable clinical phenotypes in monozygotic twins and sisters with Rett syndrome remain unexplained.
• The X-inactivation pattern is hypothesized to influence disease manifestation.

Purpose of the Study:

• To investigate the role of X-inactivation patterns in explaining variable Rett syndrome phenotypes.
• To analyze the relationship between X-inactivation skewing and clinical severity in affected siblings.

Main Methods:

• Methylation-specific PCR was used to analyze the human androgen receptor gene (polymorphic trinucleotide repeat) on Xq11.2-12.
• DNA samples from monozygotic twins, sisters, and their parents were analyzed.
• X-inactivation ratios were determined based on allele activity.

Main Results:

• In three out of four patients, the maternally derived allele was predominantly active.
• One twin patient with a near-equal ratio of active paternal and maternal alleles exhibited a much more severe phenotype.
• De novo MECP2 mutations in sporadic cases often originate from the paternal X chromosome.

Conclusions:

• A mechanism suppressing mutated paternal allele activation, leading to skewed X-inactivation and milder phenotypes, may exist.
• Failure of this suppression mechanism can result in a more severe clinical presentation of Rett syndrome.
• X-inactivation patterns are a significant factor in the variable expressivity of Rett syndrome.